This invention relates to bicyclic heterocycles that inhibit cyclin-dependent kinase or tyrosine kinase enzymes, or both, and as such are useful to treat cell proliferative disorders such as angiogenesis, atherosclerosis, restenosis, and cancer as well as immunological disorders such as asthma, rheumatoid arthritis, autoimmune diabetes, and graft rejection associated with transplant surgery in mammals.
Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate (ATP) to tyrosine residues on protein substrates. Tyrosine kinases are an integral part of growth factor receptors and are essential for the propagation of growth factor signal transduction leading to cellular proliferation, differentiation, and migration. Growth factor receptors are also known as receptor tyrosine kinases (RTKs). The aberrant regulation of growth factors or their cognate receptors plays a critical role in the progression of proliferative diseases. For example, fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) have been implicated as important mediators of tumor promoted angiogenesis (Sun L. and McMahon G., xe2x80x9cInhibition of Tumor Angiogenesis by Synthetic Receptor Tyrosine Kinase Inhibitors,xe2x80x9d Drug Discovery Today, 2000;5(8):344-353). Solid tumors are dependent upon the formation of new blood vessels from preexisting vessels (angiogenesis) to nourish their growth and to provide a conduit for metastases. Accordingly, inhibitors of the FGF and VEGF RTKs, as well as other tyrosine kinases, are useful agents for the prevention and treatment of proliferative diseases dependent on these enzymes.
Cell cycle kinases are naturally occurring enzymes involved in regulation of the cell cycle (Meijer L., xe2x80x9cChemical Inhibitors of Cyclin-Dependent Kinases,xe2x80x9d Progress in Cell Cycle Research, 1995;1:351-363). Typical enzymes include the cyclin-dependent kinases (cdk) cdk1 (also known as cdc2), cdk2, cdk4, cdk5, cdk6, and wee-1 kinase. Increased activity or temporally abnormal activation of these kinases has been shown to result in development of human tumors and other proliferative disorders such as restenosis (Fry D. and Garrett M., xe2x80x9cInhibitors of Cyclin-Dependent Kinases as Therapeutic Agents for the Treatment of Cancer,xe2x80x9d Current Opinion in Oncologic, Endocrine, and Metabolic Investigational Drugs, 2000;2(1):40-59). Compounds that inhibit cdks, either by blocking the interaction between a cyclin and its kinase partner, or by binding to and inactivating the kinase, cause inhibition of cell proliferation, and are thus useful for treating tumors or other abnormally proliferating cells.
Several compounds that inhibit cdks have demonstrated both preclinical and clinical anti-tumor activity. For example, flavopiridol is a flavonoid that has been shown to be a potent inhibitor of several types of breast and lung cancer cells (Kaur, et al., J. Natl. Cancer Inst., 1992;84:1736-1740; Int. J. Oncol., 1996;9:1143-1168). The compound has been shown to inhibit cdk2 and cdk4. Olomoucine [2-(hydroxyethylamine)-6-benzylamine-9-methylpurine] is a potent inhibitor of cdk2 and cdk5 (Vesely, et al., Eur. J. Biochem., 1994;224:771-786), and has been shown to inhibit proliferation of approximately 60 different human tumor cell lines used by the National Cancer Institute (NCI) to screen for new cancer therapies (Abraham, et al., Biology of the Cell, 1995;83:105-120).
Despite the progress that has been made, the search continues for small molecular weight compounds that are orally bioavailable and useful for treating a wide variety of human tumors and other proliferative disorders such as restenosis, angiogenesis, diabetic retinopathy, psoriasis, surgical adhesions, macular degeneration, and atherosclerosis and immunological disorders such as asthma, rheumatoid arthritis, autoimmune diabetes, and graft rejection associated with transplant surgery in mammals.
This invention provides bicyclic heterocycles that are useful for treating cell proliferative disorders, such as cancer, atherosclerosis, restenosis, angiogenesis, diabetic retinopathy, psoriasis, and endometriosis and immunological disorders. These pyridotriazine and pyridopyridazine analogs are inhibitors of tyrosine kinases and cyclin-dependent kinases (cdks). The disclosed compounds are readily synthesized and can be administered by a variety of routes, including orally and parenterally.
The compounds of the invention are members of the class of compounds of Formula I: 
and the pharmaceutically acceptable salts thereof, wherein:
W is NH, S, SO, or SO2;
X is N or CH;
Z is O, S, or NR10;
Each of R1, R2, and R10 are independently selected from the group consisting of H, (CH2)nAr, COR4, (CH2)n C3-C5 heteroaryl, (CH2)n C3-C5 heterocyclyl, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, and C2-C10 alkynyl, wherein n is 0, 1, 2, or 3, and the (CH2)nAr, (CH2)nheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 5 groups selected from NR5R6, N(O)R5R6, NR5R6R7Y, C1-C4 alkyl, phenyl, substituted phenyl, (CH2)nheteroaryl, hydroxy, C1-C4 alkoxy, phenoxy, thiol, C1-C4 thioalkyl, halo, COR5, CO2R5, CONR5R6, SO2NR5R6, SO3R5, PO3R5, C1-C5 aldehyde, nitrile, nitro, C3-C6 heteroaryloxy, T(CH2)mQR4, 
C(O)T(CH2)mQR5, NHC(O)T(CH2)mQR5, T(CH2)mC(O)NR5NR6, and T(CH2)mCO2R5 wherein each of m, mxe2x80x2, and mxe2x80x3 is independently 1-6, T is O, S, NR7, N(O)R7, NR7R8Y, or CR7R11, and Q is O, S, NR11, N(O)R11, or NR11R8Y;
R3 and R9 have the meanings of R2, wherein R2 is as defined above, as well as OH, NR12R13, COOR12, OR12, CONR12R13, SO2NR12R13, SO3R12, PO3R12, Txe2x80x2(CH2)mQxe2x80x2R4, 
wherein Txe2x80x2 and Qxe2x80x2 are as defined above for T and Q, respectively;
R4, R5, R6, R7, R11, R12, R13, R14, and R15 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, N(C1-C6alkyl)1 or 2, (CH2)nAr, C3-C10 cycloalkyl, C3-C6 heterocyclyl, and C3-C6 heteroaryl, or R5 and R6, or R7 and R8, or R12 and R13 together with the nitrogen to which they are attached optionally form a ring having 3 to 7 carbon atoms and said ring optionally contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, sulfur, and substituted sulfur; or
when R5 and R6, or R7 and R8, or R12 and R13 together with the nitrogen to which they are attached form a ring, said ring is optionally substituted by 1 to 3 groups selected from OR14, NR14R15, (CH2)mOR14, (CH2)mNR14R15, Txe2x80x3xe2x80x94(CH2)mQxe2x80x3R14, COxe2x80x94Txe2x80x3xe2x80x94(CH2)mQxe2x80x3R14, NH(CO)Txe2x80x3(CH2)mQxe2x80x3R14, Txe2x80x3xe2x80x94(CH2)mCO2R14, or Txe2x80x3(CH2)mCONR14R15; wherein Txe2x80x3 and Qxe2x80x3 are as defined above for T and Q;
R8 is C1-C6 alkyl or C3-C6 cycloallyl; and
Y is a halo counter-ion.
This invention also provides pharmaceutical formulations and pharmaceutical compositions comprising a compound of Formula I together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.
Compounds within the scope of the present invention are inhibitors of a wide variety of kinases like the cyclin-dependent kinases such as cdk2, cdc2, and cdk4 and especially of growth factor mediated tyrosine kinases including those of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), as well as non-receptor tyrosine kinases such as a transforming gene of the Rous sarcoma retrovirus (Src) family, c-Src and Lck.
As inhibitors of cyclin-dependent, as well as growth factor-mediated and non-receptor tyrosine kinases, the disclosed compounds are useful in controlling proliferative disorders such as cancer, psoriasis, diabetic retinopathy, angiogenesis, vascular smooth muscle cell proliferation, vascular smooth muscle cell proliferation associated with atherosclerosis, diabetic retinopathy, angiogenesis, postsurgical vascular stenosis and restenosis, and immunological disorders such as asthma, rheumatoid arthritis, autoimmune diabetes, and graft rejection associated with transplant surgery in mammals. As such, the present invention provides a method for treating any of the disorders mentioned above in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or of a pharmaceutical composition comprising a compound of Formula I.
A further embodiment of this invention is a method of treating subjects suffering from diseases caused by cellular proliferation. The method entails inhibiting proliferation of tumorigenic cells of epithelial origin and vascular smooth muscle proliferation, and/or cellular migration by administering a therapeutically effective amount of a compound of Formula I to a subject in need of treatment.
A further embodiment of this invention is a method of treating subjects suffering from disorders of the immune system. The method entails inhibiting protein kinases, specifically T-cell tyrosine kinase p56lck by administering a therapeutically effective amount of a compound of Formula I to a subject in need of treatment.
Another embodiment of this invention is a method for inhibiting an enzyme selected from cyclin-dependent kinases, growth factor-mediated kinases, and non-receptor tyrosine kinases, said method comprising exposing said enzyme, in vivo or in vitro, to an inhibiting amount of a compound of Formula I or a metabolite thereof.
A further embodiment of this invention is a method for treating immunological disorders associated with T-cell tyrosine kinases or with B-cell tyrosine kinases in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a compound of Formula I.
A further embodiment of this invention is a method for inhibiting a wee-1 kinase, said method comprising exposing said enzyme, in vivo or in vitro, to an inhibiting amount of a compound of Formula I or a metabolite thereof.
A further embodiment of this invention is a method of treating subjects suffering from diseases caused by DNA tumor viruses such as herpes viruses.
In addition, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing any of the disorders mentioned above.
Furthermore, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof for treating or preventing any of the disorders mentioned above.
The invention features compounds that inhibit a variety of kinases, thus the compounds are useful agents for treating subjects suffering from diseases caused by abnormal cell proliferation and diseases of the immune system. Compounds within the scope of the present invention are inhibitors of a wide variety of kinases like the cyclin-dependent kinases such as cdk2, cdc2, and cdk4 and especially of growth factor mediated tyrosine kinases including those of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), as well as non-receptor tyrosine kinases such as a transforming gene of the Rous sarcoma retrovirus (Src) family, c-Src and Lck. As inhibitors of cyclin-dependent, as well as growth factor-mediated and non-receptor tyrosine kinases, the compounds of the instant invention are useful in controlling proliferative disorders such as cancer, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, diabetic retinopathy and angiogenesis, postsurgical vascular stenosis and restenosis, and immunological disorders such as asthma, rheumatoid arthritis, autoimmune diabetes, and graft rejection associated with transplant surgery in mammals.
The present invention provides a compound of Formula I 
and the pharmaceutically acceptable salts thereof, wherein:
W is NH, S, SO, or SO2;
X is N or CH;
Z is O, S, or NR10;
Each of R1, R2, and R10 are independently selected from the group consisting of H, (CH2)nAr, COR4, (CH2)n C3-C5 heteroaryl, (CH2)n C3-C6 heterocyclyl, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, and C2-C10 alkynyl, wherein n is 0-6 and the (CH2)nAr, (CH2)nheteroaryl, heterocyclyl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 5 groups selected from NR5R6, N(O)R5R6, NR5R6R7Y, C1-C4 alkyl, phenyl, substituted phenyl, (CH2)nheteroaryl, hydroxy, C1-C4 alkoxy, phenoxy, thiol, C1-C4 thioalkyl, halo, COR5, CO2R5, CONR5R6, SO2NR5R6, SO2R5, SO3R5, PO3R5, C1-C5 aldehyde, nitrile, nitro, C3-C6 heteroaryloxy, T(CH2)mQR4, 
C(O)T(CH2)mQR5, NHC(O)T(CH2)mQR5, T(CH2)mC(O)NR5NR6, and T(CH2)mCO2R5, wherein each of m, mxe2x80x2 and mxe2x80x3 is independently 1-6, T is O, S, NR7, N(O)R7, NR7R8Y, or CR7R11, and Q is O, S, NR11, N(O)R11, or NR11 R8Y;
R3 and R9 are each OH, NR12R13, COOR12, OR12, CONR12R13, (CH2)nCOR12, (CH2)nCOOR12, halo, SO2NR12R13, SO3R12, PO3R12, Txe2x80x2(CH2)mQxe2x80x2R4, 
or as defined above for R2,
wherein Txe2x80x2 and Qxe2x80x2 are as defined above for T and Q, respectively;
R4, R5, R6, R7, R11, R12, R13, R14, and R15 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, N(C1-C6alkyl)1 or 2, (CH2)nAr, C3-C10 cycloalkyl, C3-C6 heterocyclyl, and C3-C6 heteroaryl, or R5 and R6, or R7 and R8, or R12 and R13 together with the nitrogen to which they are attached optionally form a ring having 3 to 7 carbon atoms and said ring optionally contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, sulfur, and substituted sulfur; or
when R5 and R6, or R7 and R8, or R12 and R13 together with the nitrogen to which they are attached form a ring, said ring is optionally substituted by 1 to 3 groups selected from C1-C3 alkyl, OH, OR14, NR14R15, (CH2)mOR14, (CH2)mNR14R15, Txe2x80x3xe2x80x94(CH2)mQxe2x80x3R14, COxe2x80x94Txe2x80x3xe2x80x94(CH2)mQxe2x80x3R14, NH(CO)Txe2x80x3(CH2)mQxe2x80x3R14, Txe2x80x3xe2x80x94(CH2)mCO2R14, or Txe2x80x3(CH2)mCONR14R15; wherein Txe2x80x3 and Qxe2x80x3 are as defined above for T and Q;
R8 is C1-C6 alkyl or C3-C6 cycloalkyl; and
Y is a halo counter-ion.
Preferred groups of compounds of Formula I are those wherein: (a) W is NH; (b) X is N; (c) Z is O; (d) R1 is cycloalkyl, substituted cycloalkyl, alkyl, substituted alkyl, phenyl, substituted phenyl, pyridyl, or substituted pyridyl; (e) R2 is alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; (f) R9 is hydrogen or alkyl; and (g) R3 is cycloalkyl, substituted cycloalkyl, alkyl, substituted alkyl, phenyl, substituted phenyl, pyridyl or substituted pyridyl; or more preferably, R3 is hydrogen; or (h) combinations thereof.
Another preferred groups of compounds of Formula I are those wherein: (a) W is NH; (b) X is N; (c) Z is NR10; (d) R2 is hydrogen; (e) R1 is cycloalkyl, substituted cycloalkyl, alkyl, substituted alkyl, phenyl, substituted phenyl, pyridyl, or substituted pyridyl; (f) R9 is hydrogen or alkyl; and (g) R3 is hydrogen, cycloalkyl, substituted cycloalkyl, alkyl, substituted alkyl, phenyl, substituted phenyl, pyridyl or substituted pyridyl; or (h) combinations thereof.
A further group of compounds of Formula I are those wherein: (a) W is NH; (b) X is CH; (c) Z is O or NR10; (d) R1 is cycloalkyl, substituted cycloalkyl, alkyl, substituted alkyl, phenyl, substituted phenyl, pyridyl, or substituted pyridyl; (e) R2 is alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; or, alternatively, R2 is hydrogen; (f) R9 is hydrogen or alkyl; and (g) R3 is hydrogen, cycloalkyl, substituted cycloalkyl, alkyl, substituted alkyl, phenyl, substituted phenyl, pyridyl or substituted pyridyl; or (h) combinations thereof.
Another group of compounds of Formula I are those wherein: (a) W is NH; (b) X is N; (c) Z is O or NR10, and R3 is H or substituted aryl or pyridyl; (d) R9 is hydrogen; (e) Z is O, and R2 is Me, Et, Pr, i-Pr, i-Bu, i-pentyl, or C3-C7 cycloalkyl; (f) X is CH; (g) R9 is methyl; (h) R2 is cycloalkyl and R9 is heterocyclyl; (i) R3 is (CH2)nAr; or (j) combinations thereof. In an especially preferred group of compounds, Z is O and R2 is cyclopentyl or ethyl.
In yet other preferred groups of compounds of Formula I: (h) Z is O, W is NH, and R1 is alkyl, substituted alkyl, phenyl, substituted phenyl, pyridyl or substituted pyridyl; (i) Preferred R1 substituted phenyl groups include 4-piperidinyl and 4-morpholino (with or without substitution), 4-(2-diethylaminoethoxy), 4-pyrrole, 4-pyrazol, and 4-(4-substituted piperazin-1-yl); (j) Z is O, and R1 is phenyl substituted with hydroxy, alkoxy, NR5R6, or T(CH2)mQR4. In more preferred compounds, Z is O, and R1 is pyridyl substituted with NR5R6 or T(CH2)mQR4; or Z is O, and R3 is phenyl substituted with hydroxy, alkoxy, NR5R6, or T(CH2)mQR4.
Compounds of Formula I wherein W is S, SO, or SO2 are especially useful as intermediates leading to compounds where W is NH, but such compounds also display inhibitory activity against cyclin-dependent kinases and tyrosine kinases.
Unless otherwise expressly stated, the following definitions are adhered to throughout this disclosure.
xe2x80x9cAlkylxe2x80x9d or xe2x80x9cC1-C10 alkylxe2x80x9d means a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms (unless stated otherwise) and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and the like. The term xe2x80x9cC1-C10 alkylxe2x80x9d includes within its definition, for example, the terms xe2x80x9cC1-C3 alkylxe2x80x9d, xe2x80x9cC1-C4 alkylxe2x80x9d and xe2x80x9cC1-C6 alkylxe2x80x9d.
xe2x80x9cHaloxe2x80x9d includes fluoro, chloro, bromo, and iodo.
xe2x80x9cAlkenylxe2x80x9d or xe2x80x9cC2-C10 alkenylxe2x80x9d means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and one or two double bonds and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, 3,6-octadien-1-yl, and the like. The term xe2x80x9cC2-C10 alkenylxe2x80x9d includes within its definition, for example, the terms xe2x80x9cC2-C4 alkenylxe2x80x9d and xe2x80x9cC2-C6 alkenylxe2x80x9d.
xe2x80x9cAlkynylxe2x80x9d or xe2x80x9cC2-C10 alkynylxe2x80x9d means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and one or two triple bonds and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, 3,6-octadien-1-yl, and the like. The term xe2x80x9cC2-C10 alkynylxe2x80x9d includes within its definition, for example, the terms xe2x80x9cC2-C4 alkynylxe2x80x9d and xe2x80x9cC2-C6 alkynylxe2x80x9d.
xe2x80x9cCycloalkylxe2x80x9d or xe2x80x9cC3-C10 cycloalkylxe2x80x9d means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cC3-C6 heterocyclyl,xe2x80x9d which means a cycloalkyl group also bearing at least one heteroatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine. The term xe2x80x9cC3-C10 cycloalkylxe2x80x9d includes within its definition, for example, the terms xe2x80x9cC3-C8 cycloalkylxe2x80x9d and xe2x80x9cC3-C6 cycloalkylxe2x80x9d. The term xe2x80x9cC3-C6 heterocyclylxe2x80x9d includes within its definition, for example, the xe2x80x9cC3-C5 heterocyclylxe2x80x9d.
xe2x80x9cAlkoxyxe2x80x9d or xe2x80x9cC1-C4 alkoxyxe2x80x9d refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. In addition, alkoxy refers to polyethers such as xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94OH3, and the like.
xe2x80x9cAlkanoylxe2x80x9d groups are alkyl linked through a carbonyl, i.e., C1-C9xe2x80x94C(O)xe2x80x94. Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.
xe2x80x9cAcylxe2x80x9d means an alkyl or aryl (Ar) group bonded through a carbonyl group, ie, Rxe2x80x94C(O)xe2x80x94. For example, acyl includes a C1-C10 alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like.
The alkyl, cycloalkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR5R6, N(O)R5R6, NR5R6R7Y, C1-C4 alkyl, phenyl, substituted phenyl, thio C1-C10 alkyl, C1-C10 alkoxy, hydroxy, carboxy, C1-C10 alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. xe2x80x9cSubstituted nitrogenxe2x80x9d means nitrogen bearing C1-C10 alkyl or (CH2)nPh where n is 0, 1, 2, or 3. xe2x80x9cSubstituted sulfurxe2x80x9d means sulfur bearing C1-C10 alkyl or (CH2)nPh where n is 0, 1, 2, or 3. Perhalo and polyhalo substitution is also embraced.
Examples of substituted alkyl groups include 2-aminoethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, and 2-(4-methylpiperazinyl)ethyl.
Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like.
Typical substituted alkoxy groups include 2-aminoethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
Further examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like.
The terms xe2x80x9cArxe2x80x9d and xe2x80x9carylxe2x80x9d refer to unsubstituted and substituted aromatic groups. xe2x80x9cHeteroarylxe2x80x9d or xe2x80x9cC3-C9 heteroarylxe2x80x9d groups have from 3 to 9 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, 2-pyridyl, 3-methyl-2-pyridyl, 3-benzothienyl, 2,4,6-tribromophenyl, 4-ethyl-2-benzothienyl, 2-furanyl, 3,4-diethyl-2-furanyl, 1-naphthyl, 4,7-dichloro-2-naphthyl, pyrrole, pyrazole, imidazole, thiazole, and the like. An especially preferred heteroaryl group is pyridyl. The term xe2x80x9cC3-C9 heteroarylxe2x80x9d includes within its definition, for example, the terms xe2x80x9cC3-C6 heteroarylxe2x80x9d and xe2x80x9cC3-C5 heteroarylxe2x80x9d.
The terms xe2x80x9caryloxyxe2x80x9d and xe2x80x9cheteroaryloxyxe2x80x9d, such as phenoxy and C3-C6 heteroaryloxy, refer to the aryl and heteroaryl groups, respectively, mentioned above bound through oxygen.
Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl, hydroxy, xe2x80x94COOR7, amino of the formula xe2x80x94NR5R6, CONR5R6, and T(CH2)mQR4 or T(CH2)mCO2R4 wherein m is 1 to 6, T is O, S, NR4, N(O)R4, NR5R6Y, or CR4R5, Q is O, S, NR5, N(O)R5, or NR5R6Y wherein R4, R5 and R6, are as described above, and R7 is H, alkyl or substituted alkyl, for example, methyl, 2-aminoethyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxy groups can be substituted as defined above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl.
The invention compound will be named herein according to the following position assignments 
It will be appreciated by those skilled in the art that the compounds defined by the Formula I can exist in tautomeric forms. For example, a 6-keto compound can tautomerize to a 6-enol when R2 is hydrogen as follows: 
Similarly, 6-imino compounds can tautomerize to 6-amino compounds as follows: 
6-Thiones can tautomerize to thiols as follows: 
All of the tautomeric forms of the compounds are contemplated and included within the scope of this invention.
The compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The compounds of Formula I are capable of further forming both pharmaceutically acceptable formulations comprising salts, including but not limited to acid addition and/or base salts, solvates and N-oxides. This invention also provides pharmaceutical formulations and compositions comprising a compound of Formula I together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. All of these forms are within the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived form inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharmaceutical Science, 1977;66:1-19.
The acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention. Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine; see, for example, Berge, et al., supra.
The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
The term xe2x80x9csubjectxe2x80x9d means all animals, preferably mammals, including humans. Examples of subjects or mammals include humans, cows, dogs, cats, goats, sheep, and pigs.
The term xe2x80x9ctreatingxe2x80x9d for purposes of the present invention refers to prophylaxis or prevention, amelioration or elimination of a named disease or disorder once the disorder has been established.
The compounds of the present invention are useful for treating immunological disorders (for example, asthma, inflammatory disorders such as rheumatoid arthritis, autoimmune disorders such as autoimmune diabetes, and graft rejection associated with transplant surgery), cancer (for example, leukemia and cancer of the lung, breast, prostate, and skin such as melanoma) and other proliferative diseases including but not limited to angiogenesis, diabetic retinopathy, endometriosis, vascular smooth muscle cell proliferation, vascular smooth muscle cell proliferation associated with atherosclerosis, postsurgical vascular stenosis, psoriasis, surgical adhesions, macular degeneration, HSV, HIV, restenosis, and atherosclerosis. To utilize a compound of the present invention to treat cancer, a patient having cancer is administered a therapeutically effective amount of a disclosed compound or a pharmaceutically acceptable composition comprising the disclosed compound.
A further embodiment of this invention is a method of treating subjects suffering from diseases caused by vascular smooth muscle cell proliferation. Compounds within the scope of the present invention effectively inhibit vascular smooth muscle cell proliferation and migration. The method entails inhibiting vascular smooth muscle proliferation, and/or migration by administering an effective amount of a compound of Formula I to a subject in need of treatment.
The compounds of the present invention can be formulated and administered in a wide variety of oral and parenteral dosage forms, including transdermal and rectal administration. It will be recognized to those skilled in the art that the following dosage forms may comprise as the active component, a compound of Formula I or a corresponding pharmaceutically acceptable salt or solvate thereof.
A further embodiment of this invention is a pharmaceutical formulation comprising a compound of Formula I together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. For preparing pharmaceutical compositions with the compounds of the present invention, pharmacuetically acceptable carriers can be either a solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid such as talc or starch which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The formulations of this invention preferably contain from about 5% to about 70% or more of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. A preferred form for oral use are capsules, which include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogenously therein, as by stirring. The molten homogenous mixture is then poured into convenient size molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions such as water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution, isotonic saline, 5% aqueous glucose, and the like. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water and mixing with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. Waxes, polymers, microparticles, and the like can be utilized to prepare sustained-release dosage forms. Also, osmotic pumps can be employed to deliver the active compound uniformally over a prolonged period. The disclosed compounds can also be formulated as powders or liquids to be inhaled.
The pharmaceutical preparations of the invention are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The therapeutically effective dose or amount of a compound of Formula I will generally be from about 1 mg to about 100 mg/kg of body weight per day. Typical adult doses will be about 50 mg to about 800 mg per day. The quantity of active component in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 500 mg, preferably about 0.5 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents. A subject in need of treatment with a compound of Formula I is administered a dosage of about 1 to about 500 mg per day, either singly or in multiple doses over a 24-hour period.
The compounds of the present invention are capable of binding to and inhibiting the activity of proteins having the ability to phosphorylate other proteins, such as cdks, PDGFr, FGFr, VEGF, c-Src, Lck and EGFr-FL. The compounds of this invention inhibit this phosphorylation and therefore can be used as anti-proliferative agents for the treatment of cancer and/or restenosis and other proliferative diseases.
Because of their inhibitory activity against cdks and other kinases, the compounds of the present invention are also useful research tools for studying the mechanism of action of those kinases, both in vitro and in vivo.
While the forms of the invention herein constitute presently preferred embodiments, many others are possible. It is not intended herein to mention all of the possible equivalent forms or ramifications of the invention. It is understood that the terms used herein are merely descriptive rather than limiting, and those skilled in the art will realize that various changes may be made without departing from the spirit or scope of the invention.
The following compounds illustrate specific embodiments provided by the present invention, and the compounds listed below are among the preferred embodiments:
5-Cyclopentyl-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-8-methyl-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
4-(5-Cyclopentyl-6-oxo-5,6-dihydro-pyrido[2,3-e]-1,2,4-triazin-3-ylamino)-benzenesulfonamide;
4-(5-Cyclopentyl-8-methyl-6-oxo-5,6-dihydro-pyrido[2,3-e]-1,2,4-triazin-3-ylamino)-benzenesulfonamide;
5-Cyclopentyl-3-(4-piperazin-1-yl-phenylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
4-[4-(5-Cyclopentyl-6-oxo-5,6-dihydro-pyrido[2,3-e]-1,2,4-triazin-3-ylamino)-phenyl]-piperazine-1-carboxylic acid amide;
5-Cyclopentyl-8-methyl-3-(4-piperazin-1-yl-phenylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
4-[4-(5-Cyclopentyl-8-methyl-6-oxo-5,6-dihydro-pyrido[2,3-e]-1,2,4-triazin-3-ylamino)-phenyl]-piperazine-1-carboxylic acid amide;
5-Cyclopentyl-3-[4-(3,5-dimethyl-piperazin-1-yl)-phenylamino]-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
4-[4-(5-Cyclopentyl-6-oxo-5,6-dihydro-pyrido[2,3-e]-1,2,4-triazin-3-ylamino)-phenyl]-2,6-dimethyl-piperazine-1-carboxylic acid amide;
5-Cyclopentyl-3-[4-(3,5-dimethyl-piperazin-1-yl)-phenylamino]-8-methyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
4-[4-(5-Cyclopentyl-8-methyl-6-oxo-5,6-dihydro-pyrido[2,3-e]-1,2,4-triazin-3-ylamino)-phenyl]-2,6-dimethyl-piperazine-1-carboxylic acid amide;
7-(2-Chloro-3,5-dimethoxy-phenyl)-5-ethyl-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(2,6-Dichloro-3,5-dimethoxy-phenyl)-5-ethyl-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(3,5-Dimethoxy-2-methyl-phenyl)-5-ethyl-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(3,5-Dimethoxy-phenyl)-5-ethyl-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(3,5-Dimethoxy-2,6-dimethyl-phenyl)-5-ethyl-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-7-(3,5-dimethoxy-phenyl)-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(2-Chloro-3,5-dimethoxy-phenyl)-5-cyclopentyl-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-7-(3,5-dimethoxy-2-methyl-phenyl)-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-7-(3,5-dimethoxy-2,6-dimethyl-phenyl)-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(2,6-Dimethoxy-pyridin-4-yl)-5-ethyl-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(3-Chloro-2,6-dimethoxy-pyridin-4-yl)-5-ethyl-3-(pyridin-4-ylamino)-5H-pyrido [2,3-e]-1,2,4-triazin-6-one;
7-(3,5-Dichloro-2,6-dimethoxy-pyridin-4-yl)-5-ethyl-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-7-(2,6-dimethoxy-pyridin-4-yl)-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(3-Chloro-2,6-dimethoxy-pyridin-4-yl)-5-cyclopentyl-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-7-(3,5-dichloro-2,6-dimethoxy-pyridin-4-yl)-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(2-Chloro-3,5-dimethoxy-phenyl)-3-[4-(2-diethylamino-ethoxy)-phenylamino]-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[4-(2-diethylamino-ethoxy)-phenylamino]-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
3-[4-(2-Diethylamino-ethoxy)-phenylamino]-7-(3,5-dimethoxy-2-methyl-phenyl)-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
3-(4-Diethylamino-butylamino)-7-((3,5-dimethoxy-phenyl)-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
3-[4-(2-Diethylamino-ethoxy)-phenylamino]-7-(3,5-dimethoxy-2,6-dimethyl-phenyl)-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-3-[4-(2-diethylamino-ethoxy)-phenylamino]-7-(3,5-dimethoxy-phenyl)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(2-Chloro-3,5-dimethoxy-phenyl)-5-cyclopentyl-3-[4-(2-diethylamino-ethoxy)-phenylamino]-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-[4-(2-diethylamino-ethoxy)-phenylamino]-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-3-[4-(2-diethylamino-ethoxy)-phenylamino]-7-(3,5-dimethoxy-2-methyl-phenyl)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-3-[4-(2-diethylamino-ethoxy)-phenylamino]-7-(3,5-dimethoxy-2,6-dimethyl-phenyl)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
3-[4-(2-Diethylamino-ethoxy)-phenylamino]-7-(2,6-dimethoxy-pyridin-4-yl)-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(3-Chloro-2,6-dimethoxy-pyridin-4-yl)-3-[4-(2-diethylamino-ethoxy)-phenylamino]-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(3,5-Dichloro-2,6-dimethoxy-pyridin-4-yl)-3-[4-(2-diethylamino-ethoxy)-phenylamino]-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(2-Chloro-3,5-dimethoxy-phenyl)-3-(4-diethylamino-butylamino)-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-(4-diethylamino-butylamino)-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
3-(4-Diethylamino-butylamino)-7-(3,5-dimethoxy-2-methyl-phenyl)-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
3-(4-Diethylamino-butylamino)-7-(3,5-dimethoxy-2,6-dimethyl-phenyl)-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-3-(4-diethylamino-butylamino)-7-(3,5-dimethoxy-phenyl)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(2-Chloro-3,5-dimethoxy-phenyl)-5-cyclopentyl-3-(4-diethylamino-butylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(4-diethylamino-butylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-3-(4-diethylamino-butylamino)-7-(3,5-dimethoxy-2-methyl-phenyl)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-3-(4-diethylamino-butylamino)-7-(3,5-dimethoxy-2,6-dimethyl-phenyl)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
3-(4-Diethylamino-butylamino)-7-(2,6-dimethoxy-pyridin-4-yl)-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(3-Chloro-2,6-dimethoxy-pyridin-4-yl)-3-(4-diethylamino-butylamino)-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(3,5-Dichloro-2,6-dimethoxy-pyridin-4-yl)-3-(4-diethylamino-butylamino)-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-3-(4-diethylamino-butylamino)-7-(2,6-dimethoxy-pyridin-4-yl)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-(3-Chloro-2,6-dimethoxy-pyridin-4-yl)-5-cyclopentyl-3-(4-diethylamino-butylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
5-Cyclopentyl-7-(3,5-dichloro-2,6-dimethoxy-pyridin-4-yl)-3-(4-diethylamino-butylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one;
7-Acetyl-5-cyclopentyl-8-methyl-3-(4-piperazin-1-yl-phenylamino)-5H-pyrido[2,3-e][1,2,4]triazin-6-one;
5-Cyclopentyl-8-methyl-6-oxo-3-(4-piperazin-1-yl-phenylamino)-5,6-dihydro-pyrido[2,3-e][1,2,4]triazine-7-carboxylic acid ethyl ester;
7-Acetyl-5-cyclopentyl-3-(4-piperazin-1-yl-phenylamino)-5H-pyrido[2,3-e][1,2,4]triazin-6-one;
7-Benzyl-5-cyclopentyl-3-(4-piperazin-1-yl-phenylamino)-5H-pyrido[2,3-e][1,2,4]triazin-6-one;
7-Benzyl-5-cyclopentyl-3-(4-piperazin-1-yl-cyclohexylamino)-5H-pyrido[2,3-e][1,2,4]triazin-6-one;
7-Benzyl-5-cyclopentyl-3-(4-dimethylamino-cyclohexylamino)-5H-pyrido[2,3-e][1,2,4]triazin-6-one;
7-Bromo-5-cyclopentyl-3-(4-piperazin-1-yl-phenylamino)-5H-pyrido[2,3-e][1,2,4]triazin-6-one;
7-Bromo-5-cyclopentyl-8-methyl-3-(4-piperazin-1-yl-phenylamino)-5H-pyrido[2,3-e][1,2,4]triazin-6-one;
7-Benzyl-5-cyclopentyl-3-(1-propyl-piperidin-4-ylamino)-5H-pyrido[2,3-e][1,2,4]triazin-6-one;
7-Benzyloxy-5-cyclopentyl-3-(4-piperazin-1-yl-phenylamino)-5H-pyrido[2,3-e][1,2,4]triazin-6-one;
5-Cyclopentyl-7-ethyl-3-(4-piperazin-1-yl-phenylamino)-5H-pyrido[2,3-e][1,2,4]triazin-6-one;
5-Cyclopentyl-3-(4-piperazin-1-yl-phenylamino)-7-propoxy-5H-pyrido[2,3-e][1,2,4]triazin-6-one;
5-Cyclopentyl-3-(4-piperazin-1-yl-phenylamino)-7-o-tolylamino-5H-pyrido[2,3-e][1,2,4]triazin-6-one;
5-Cyclopentyl-7-(4-methoxy-phenylamino)-3-(4-piperazin-1-yl-phenylamino)-5H-pyrido[2,3-e][1,2,4]triazin-6-one; and
5-Cyclopentyl-7-(2-ethoxy-ethoxy)-3-(4-piperazin-1-yl-phenylamino)-5H-pyrido[2,3-e][1,2,4]triazin-6-one.
7-(3,5-Dimethoxy-phenyl)-5-ethyl-3-(pyridin-4-ylamino)-5H-pyrido[2,3-e]-1,2,4-triazin-6-one.
3-(4-Diethylamino-butylamino)-7-(3,5-dimethoxy-phenyl)-5-ethyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one.
Compounds of Formula I wherein X is N or CH may be prepared according to the syntheses outlined in Schemes 1-3. Although these schemes often indicate exact structures, those with ordinary skill in the art will appreciate that the methods apply widely to analogous compounds of Formula I, given appropriate consideration to protection and deprotection of reactive functional groups by methods standard to the art of organic chemistry. For example, hydroxy groups, in order to prevent unwanted side reactions, generally need to be converted to ethers or esters during chemical reactions at other sites in the molecule. The hydroxy protecting group is readily removed to provide the free hydroxy group. Amino groups and carboxylic acid groups are similarly derivatized to protect them against unwanted side reactions. Typical protecting groups and methods for attaching and cleaving them are described fully by Greene and Wuts in Protective Groups in Organic Synthesis, John Wiley and Sons, New York, (2nd Ed., 1991), and McOmie, Protective Groups in Organic Chemistry, Plenum Press, New York, 1973.
Scheme 1 describes a typical method for the preparation of the compounds of the invention illustrated by Formula II 
The synthesis begins with the acid catalyzed coupling of diethyl ketomalonate and thiosemicarbazide in ethanol. To the cooled reaction is added sodium metal to complete the cyclization to provide 5-hydroxy-3-mercapto-1,2,4-triazine-6-carboxylic acid ethyl ester. Alkylation of the sulfur with an alkylating agent such as methyl iodide and a common base such as potassium carbonate in a solvent like dimethylformamide affords 5-hydroxy-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid ethyl ester. Transformation of the hydroxy group to chloro with thionylchloride gives a key intermediate to which amino groups can be added to provide 5-alkylamino-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid, ethyl ester. The amine used can be anhydrous or in an aqueous solution, as with methyl or ethyl amine, or cyclopentylamine. The use of aqueous ammonium hydroxide provides the corresponding primary amine at C-5 position. Conversion of the ester group to an aldehyde can be accomplished by reduction to the alcohol with a reducing agent such as lithium aluminum hydride in a solvent like tetrahydrofuran followed by mild oxidation with manganese dioxide to provide 5-alkylamino-3-methylsulfanyl-1,2,4-triazine-6-carbaldehyde. Cyclization is accomplished by the reaction of the above triazine with an agent such as substituted phenyl acetonitrile and a base such as potassium carbonate in a solvent like tetrahydrofuran. Hydrolysis of the resulting C-6 imine under mild acidic reaction conditions gives 7-substituted phenyl-5-alkyl-3-methylsulfanyl-pyrido-1,2,4-triazin-6-one. Ultimately, the 7-substituted phenyl-5-alkyl-3-amino-pyrido-1,2,4-triazin-6-one is obtained by the reaction of the methylthio compound with an amine with or without a solvent. The temperature and conditions required for the displacement depends upon the amine used. Aromatic, secondary, and tertiary amines usually require higher temperatures than primary aliphatic or benzyl amines. When aromatic amines such as aniline or aminopyridine are used, the reaction is usually run with the amine as the solvent at high temperatures (e.g., 80-150xc2x0 C.).
Scheme 2 describes how another set of preferred compounds of this invention, illustrated by Formula III 
can be prepared if ammonia is used to displace the chloro group of 5-chloro-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid, ethyl ester to give 5-amino-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid, ethyl ester. The aldehyde is obtained and reacted with a substituted phenyl acetonitrile as described above to provide the 6-amino-pyridotriazines. The methylthio group is displaced as described above, also, and the 6-amino group of the resulting 6-amino-7-substituted phenyl-3-substituted amino-pyrido-1,2,4-triazine is derivatized by standard methods, for example alkylation or acylation, to provide compounds of Formula III.
Scheme 3 describes a typical method for the preparation of yet another set of compounds of this invention, illustrated by Formula IV 
The synthesis begins with the coupling of hydrazine and the dialkyl ester of chloromaleic acid followed by the conversion of the resulting carbonyl groups to chloro groups with phosphorous oxychloride to give the 3,4,6-trichloropyridazine. Displacement of the chloro group at C-4 with a primary amine like ethylamine or cyclopentylamine in a solvent like diethyl ether or dichloromethane at cool reaction temperature (for example below 0xc2x0 C.) followed by the displacement of the chloro group at C-6 with another appropriate primary amine like aniline or 4-aminopyridine provides the intermediate whereby the C-4 and C-6 positions of the pyridazine are appropriately substituted with amino groups. Halogen exchange of the remaining chloro group at C-3 to iodo in a heated reaction with KI in DMSO or by the reaction of butyllithium and iodine gives the 3-iodo intermediate that is transformed to the carboxaldehyde via a palladium catalyzed carbonylation utilizing carbon monoxide and tributyltin hydride. The resulting 4,6-diaminopyridazine-3-carboxaldehyde is then converted to compounds of Formula IV where R3 is H via Horner-Emmons reaction conditions or where R is a substituent like an aryl group via Aldol reaction conditions such as potassium carbonate in dimethylformamide or sodium hydride in tetrahydrofuran.
Pyrido[2,3-e][1,2,4]triazinin-6-ones are available through the route illustrated in Scheme 4. The intermediate aldehyde from Scheme 1 may be converted under Homer Emmons or aldol conditions to the pyridotriazinone with various substituents R3. Straight displacement of the sulfide with strong nucleophiles such as primary amines or initial conversion of the sulfide to the chloride followed by displacement of Cl will produce the final product. Compounds with substituents at R9 are similarly available after first converting the aldehyde to a ketone via a Grignard reaction/oxidation sequence. Halogenated products may be further converted to ethers, esters, ketones and amines as shown in Schemes 5-8. 
All of the disclosed compounds are readily purified by standard methods when desired. Typical purification steps employed include chromatography over solid supports such as silica gel or alumina. Elution generally is carried out using common solvents such as acetone, ethyl acetate, tetrahydrofuran, ethanol, triethylamine, and mixtures of such solvents. Other purification processes can similarly be employed, including crystallization from common solvents such as methanol, ethanol, diethyl ether, ethyl acetate, and the like. Sometimes such crystallizations can afford solvates such as an ethanol solvate, as well as hydrates, and all such solvates and hydrates are included in the scope of this invention.
The foregoing general reaction schemes are further described by the following detailed examples which are for illustrative purposes only and are not intended, nor should they be construed, as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications can be made without violating the spirit or scope of the invention.